Odynophagia as the first manifestation of toxic epidermal necrolysis
- Noelia Ortega Beltrá 1,
- Fernando Guallart Domenech 1,
- Paula Martínez Ruiz de Apodaca 1 , 1 and
- Francisco Pons Rocher 1 , 2
- 1 Otorhinolaryngology, Hospital Universitario Doctor Peset, Valencia, Spain
- 2 Cirurgia (Otorhinolaryngology), Universitat de Valencia Facultat de Medicina i Odontologia, Valencia, Spain
- Correspondence to Dr Francisco Pons Rocher; francisco.rocher@uv.es
Abstract
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are infrequent mucocutaneous diseases, rapidly progressive and life-threatening. The clinical aspects and the management of TEN are exposed following a case.
A man in his 40s presented to the emergency department with severe odynophagia, poor general condition and fever. His medical history was significant for HIV stage AIDS, and the treatment was discontinued 5 years before the present diagnosis. He was admitted for cerebral toxoplasmosis and discharged the previous 14 days with sulfadiazine. Erythematous-bullous lesions in the oral cavity, diffuse erythematous maculopapular rashes over his neck and chest, acute bilateral conjunctivitis and purulent urethritis was observed. The diagnostic suspicion was SJS/TEN due to sulfadiazine in immunosuppressed patients.
This entity is infrequent but is a life-threatening dermatological emergency that requires immediate medical attention. Its diagnosis is mainly clinical, with a new drug history, prodromal symptoms and characteristic cutaneous–mucous lesions. Early diagnosis and rapid withdrawal of the drug improve the prognosis.
Background
The global incidence of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is 0.4–1.2 cases/million people per year.1 2 It varies from 1.9 cases per million in Europe to 6.5 cases per million in Asia.3
The incidence of SJS/TEN in patients with HIV is higher than in the rest of the patients (0.95–1 per 1000 people).4 5 Mittmann et al report an incidence of SJS/TEN of 5–7 per 3710 or approximately 1–2 per 1000 HIV-positive people in their cohort.2
Tseng et al carried out a retrospective analysis of patients with HIV diagnosed with TEN from 2001 to 2014. They identified 10 cases of TEN, 50% were HIV positive, and the most frequent causal drug was trimethoprim/sulfamethoxazole (TMP/SMX). These authors warn of possible inappropriate use of antibiotics in a population susceptible to severe adverse drug reactions.6
Case presentation
A man in his 40s, whose medical history was significant for HIV stage AIDS, had treatment abandonment 5 years before.
He was admitted for cerebral toxoplasmosis and discharged with a treatment with sulfadiazine during 14 days. There was no known history of malignancy. The patient denied any known drug allergies.
After the treatment of 14 days with sulfadiazine, he presented to the emergency department with severe odynophagia, poor general condition and fever. He had a low-grade fever (37.6°C) with a pulse rate of 80/min and blood pressure of 128/79 mm Hg.
Investigations
Because of erythema in the oropharynx and both ears, an ear, nose and throat evaluation was requested. Erythematous-bullous lesions in the oral cavity, cracks and scabs in vermilion, erythema and painful oedema in both ears were observed. Given these findings, the patient was re-examined. Diffuse erythematous maculopapular rashes over his neck and chest, nail involvement, acute bilateral conjunctivitis and purulent urethritis was observed. Nikolsky’s sign was positive (see figure 1).
The patient in the emergency room. (A) Maculopapular lesions on the chest. (B) Maculopapular lesions on ears and neck. (C) Oral bullous lesions.
Laboratory tests revealed elevated acute phase reactants (erythrocyte sedimentation rate, C reactive protein, fibrinogen and lactate dehydrogenase), white cell count of 6800 109/L, haemoglobin of 12.1 g/L and a platelet count of 146 000109/L . Serum electrolytes, coagulation, kidney and liver parameters were normal. Serology was negative for COVID-19, Mycoplasma pneumoniae and human herpes virus.
Blood, urine and wound cultures were sent. His chest X-ray was unremarkable.
Differential diagnosis
The authors consider other differential diagnoses, such as pemphigus vulgaris or staphylococcal scalded skin syndrome.
Treatment
The diagnostic suspicion was SJS/TEN due to sulfadiazine in immunosuppressed patients. The use of sulfadiazine was stopped immediately. He was managed with fluid therapy, intravenous corticosteroids and burned patient care.
Outcome and follow-up
The lesions progressed into blisters during admission, followed by diffuse exfoliation of skin involving the face, ears, neck and chest, affecting 35% of the body surface area (see figure 2). He was haemodynamically stable with clinical improvement. His hospital course was not complicated, with an adequate response to steroid therapy. The patient had remarkable regeneration of skin and was discharged after 2 weeks.
The patient during admission. (A) Progression to blistering and scaling lesions of greater extension on face, neck and chest. (B) Blisters on ears and head. (C) Evolution of oral lesions. (D) Nail involvement.
Discussion
Most TEN cases are related to drugs (80%–95%).7 Several drugs have a high risk of inducing SJS/TEN, such as allopurinol, antibiotics (sulfonamides like TMP/SMX, aminopenicillins, cephalosporins, quinolones), antiepileptics (carbamazepine, phenytoin, phenobarbital) and non-steroidal anti-inflammatory drugs (oxicams).2 3 7 8 Sulfonamides are implicated in approximately 30% of drug-induced cases, especially TMP/SMX. The TEN can occur from 1 to 13 days after starting the TMP/SMX.7 Roujeau et al published a retrospective analysis of 245 people admitted to the hospital with a TEN diagnosis. Sulfonamides, especially TMP/SMX, achieved the highest risk (risk ratio=175).1
Other potential aetiologies include infections such as HIV, M. pneumoniae and human herpes virus, and also malignant diseases such as hepatocellular and lung carcinoma.7 8
More recently, it has been reported in patients with COVID-19 due to the infection or the medications used to treat it.9–11
Many recent studies have found an association between different HLA (human leukocyte antigen) alleles and the development of TEN, especially in the Asian population.8 12 13
The pathogenesis is unknown, although it has been associated with defects in drug metabolism or cytotoxic reactions. Patients who develop TEN induced by sulfonamides have been characterised as slow acetylators. They cannot remove the metabolite, which accumulates and binds to epidermal cells and induces an immune response. Cytotoxicity mediated by CD4+ and CD8+ T cells, macrophages, tumour necrosis factor (TNF) and nitric oxide causes apoptosis.14
Sulfonamides are associated with a significant number of cases of SJS/TEN in patients with HIV.2 15
Although this predominance can be justified by the increased use of sulfonamides in patients with HIV,7 Yang et al found a decrease in the number of skin-directed CD41 cells and an increase in the ratio of CD81/CD41 cells in TEN lesions in patients with HIV. This likely contributes to increased risk because of the loss of skin-protective CD41/CD251 regulatory T cells.16
This disease presents epidermal and mucosal necrosis. First, patients usually present with a prodrome of fever, bad general state, headache, diarrhoea, odynophagia and arthralgia for 1–14 days.7 Later, a macular rash appears like large target lesions on the face, neck, chin and trunk, and progressively spreads to the extremities. They turn into haemorrhagic erosions, more or less severe epidermal detachment, with blisters and areas of denuded skin, being the Nikolski’s sign positive. Such lesions tend to coalesce in large areas. Authors make a difference between entities according to the proportion of epidermal detachment: less than 10% of the body surface in SJS and more than 30% in TEN. SJS/TEN overlay is used for intermediate cases.2 3 7 8
These bullous lesions can also appear on the mucous membranes. In decreasing order of frequency, these areas are the oral cavity and oropharynx, the bulbar conjunctiva and the anogenital area. Mucosal involvement may occur before or parallel to the skin rash.7
A systemic involvement may happen with anaemia, thrombocytopenia, neutropenia, elevated liver function tests and electrolyte imbalances.7
Diagnosis is based mainly on clinical signs. The presence of a characteristic clinical picture that appears with the administration of a drug and disappears after its withdrawal could obviate the histological study.17 18 In addition, recent advances in the study of serum levels of diagnostic biomarkers could obviate the histological study.19 However, histological confirmation, with a skin biopsy showing typical full-thickness epidermal necrolysis due to extensive apoptosis of keratinocytes, may exclude other entities.7 8
The differential diagnosis includes linear IgA dermatosis, paraneoplastic pemphigus, pemphigus vulgaris, bullous pemphigoid, acute generalised exanthematous pustulosis, disseminated bullous fixed drug eruption and staphylococcal scalded skin syndrome.8
An early diagnosis is required. Once the drug has been identified and disrupted, these patients need symptomatic support with intravenous fluid replacement in a burn unit or intensive care unit. In addition, pain management, nutritional support with a nasogastric tube and sepsis control are essential. Prophylactic antibiotics are not recommended and should be reserved for clinically suspected infection. Oral mucosal lesions can be treated with an antiseptic or antifungal solution, and the lips should be lubricated with an ointment.7 19 It is also very important to ask about dysuria because of the risk of urethritis and synechiae in the genital mucosa. Another of the most frequent sequelae is ophthalmic involvement with corneal ulcers and conjunctival synechiae. To avoid them, daily cleaning with saline solution is recommended, followed by the application of antibiotics and corticosteroids in eye drops and ointment every 6 hours, hyaluronic acid gel and artificial tears as required.
The most common medical treatment for SJS/TEN is systemic corticosteroids (1.5 mg/kg intravenous dexamethasone administered over 30–60 min for 3 consecutive days).20 Other publications have also reported the beneficial use of ciclosporin and anti-TNF biological agents (etanercept) in SJS/TEN.21 22 In contrast, the use of intravenous immunoglobulins does not yield survival benefits.23
In this case, only intravenous corticosteroids were administered in monotherapy without biological drugs due to the risk of immunosuppression in a patient with poorly controlled HIV with cerebral toxoplasmosis. Given the good response with the suppression of the responsible drug and with corticosteroids, it was not necessary to add an adjuvant drug.
This diagnosis is a life-threatening dermatological emergency that requires immediate medical attention. For SJS, the estimated mortality is 1%–5%, while for TEN, it is higher, 25%–35%, due to greater body surface extension and severity.3
The most common cause of death in SJS/TEN in the acute stage is septicaemia.19
Predictors of mortality include patients over the age of 40 years, percentage of skin detachment and serum urea nitrogen concentration.8 14
A severity scale called SCORTEN should be used to evaluate the prognosis of these diseases.8
More than 50% of survivors suffer from long-term effects such as changes in pigmentation and scarring of the skin, visual disability, sicca syndrome, periodontal disease, gastrointestinal ulceration, vaginal and urethral stenosis, or increased autoimmunity.3 8
Patient’s perspective
I am very happy with the treatment and professionalism received from the medical team. Thanks to the prompt diagnosis I was able to recover without major complications.
Learning points
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In the differential diagnosis of odynophagia with oral macular-bullous lesions, we must also consider systemic diseases, mainly Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), because of their severity.
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SJS and TEN are infrequent but life-threatening and originated because of an adverse drug reaction process.
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Antibiotics, including trimethoprim/sulfamethoxazole, are most often associated with these entities.
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Immunocompromised patients, such as those with HIV, are more prone to their development.
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SJS/TEN diagnosis is mainly clinical, with a history of a new drug, prodromal symptoms and characteristic cutaneous–mucous lesions. Early diagnosis and rapid withdrawal of the drug improve the prognosis.
Ethics statements
Patient consent for publication
Acknowledgments
Work by these authors was partially supported by the Universitat de València. The authors are grateful for their support on research and publication.
Footnotes
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Contributors NOB—conception and design, reporting and writing of the manuscript and draft preparation, acquisition of data, analysis and interpretation of data. FGD—planning the therapeutic conduct of the patient disease, search and development of multimedia resources for the paper. PMRdA—methodology, analysis and interpretation of data, writing (review and editing), language review. FPR—conception and design, reporting, writing (review and editing), institutional link. All authors have read and agreed to the published version of the manuscript.
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Funding This study was supported by Universitat de València (200177).
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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